Systematical comparison reveals distinct brain transcriptomic features in models of depression induced by gut microbiota dysbiosis and chronic stress

Major depressive disorder (MDD) is a devastating psychiatric illness caused by various etiologies. Both chronic stress and gut microbiome dysbiosis are implicated in the pathogenesis of MDD. However, limited research was undertaken to delineate the distinct effects of these two pathogenic factors on the brain transcriptome. We generated and compared transcriptomic features of anterior cingulate cortex (ACC) from depressive-like mice induced by gut microbiome dysbiosis and canonical chronic stress paradigms, including gene expression pattern and network characteristics. The data derived from MDD patients served as a reference standard to filter the molecular alterations associated with the disorder. Chronic stress induced a plethora of altered genes and biological functions associated with depression, central to which are mitochondrial dysfunction. However, gut microbiota dysbiosis specifically regulated a limited scope of genes and biological mechanisms, targeting the aberrations in vesicular transport systems and the perturbation of autophagy pathways. Network analysis revealed that hierarchical gene co-expression specifically affected by gut microbiota dysbiosis, rather than chronic stress. The further functional clustering analysis and the central distribution of the inflammation-related differentially expressed genes suggested the intricate interplay between disrupted autophagy processes, microglia-mediated inflammation, and synaptic dysfunctions in the network influenced by gut microbiota dysbiosis. Our findings revealed the distinctive transcriptomic alterations of brain shaped by gut microbiota and chronic stress in development of MDD and contributed to understanding the heterogeneity of depression. Additionally, we have provided a valuable data resource and bioinformatic analysis template for further studies.